Preparation of thiocycloalkno [3,2-b] pyridines

ABSTRACT

Novel substituted thiacycloalkeno [3,2-b] pyridines are described. These compounds are useful as calcium channel antagonists with cardiovascular, antiasthmatic and antibronchoconstrictor activity.

This is a division of application Ser. No. 010,858, filed Feb. 17, 1987, now U.S. Pat. No. 4,777,167, which is a continuation-in-part of application Ser. No. 849,647, filed Apr. 9, 1986, now U.S. Pat. No. 4,705,785.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention realtes to certain substituted thiacycloalkeno [3,2-b] pyridines. These compounds are useful as calcium channel antagonists with cardiovascular, antiasthmatic, antibronchospastic, gastric antisecretory, cytoprotective and platelet aggregation inhibitory activity. In addition, the compounds are useful in treating hypermotility of the G-I tract and in the treatment of diarrhea. This invention also relates to a process for preparing these compounds, compositions thereof, methods of use and novel intermediates.

2. Related Disclosure

U.S. Pat. No. 4,285,955 and U.S. Pat. No. 4,483,985 (which is a divisional of the aforementioned patent) disclose acyclic sulfone substitution on simple dihydropyridines which possess calcium channel antagonist activity. However, the compounds in question are chemically distinct from the compounds of the present invention.

10-Phenyl-2H-thipyrano[3,2-b]quinolines are disclosed in G. P. A. Pagani, J.Chem.Soc., Perkin Trans.2,1392-7(1974).

However, these compounds are not calcium channel antagonists.

U.S. Pat. No. 4532248 discloses a broad genus of dihydropyridines including cyclic sulfones fused to a dihydropyridine nucleus. Cardiotonic activity is claimed for the entire genus. The compounds of the present invention, on the other hand, are potent calcium antagonists with pharmacologic activity opposite to that claimed in U.S. Pat. No. 4,532,248.

SUMMARY OF THE INVENTION

The substituted thiacycloalkeno [3,2-b] pyridines which are the subject of this invention have the following general formula: ##STR1## wherein n is an integer from 1 to 12; R₁ is hydrogen, amino, alkyl, haloalkyl or CH₂ OR₂ ; R₂ is straight chained or branched alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or alkylene-X having at least 2 carbon atoms, wherein X is alkoxy, hydroxy, halo, p-tosyloxy, mesyloxy, amino, pyridyl or --NR₄ R₅, wherein R₄ and R₅ are the same or different and are selected from hydrogen, alkyl, cycloalkyl, phenyl, benzyl, phenylethyl, or R₄, R₅ and the nitrogen atom to which they are attached form a 5, 6 or 7 membered heterocyclic ring which optionally contains an oxygen or sulfur atom or an additional nitrogen atom or said heterocyclic ring may be fused to a benzene ring, as in indoline, isoindoline, tetrahydroquinoline or tetrahydroisoquinoline, and in the instance wherein said heterocyclic ring is piperazino, said piperazino may optionally be substituted in the 4- position with the substituent R₆ which is selected from alkyl, cycloalkyl, benzyl, phenyl, or phenyl substituted by alkoxy, halo, alkyl, nitro or trifluoromethyl; R₃ is 2-pyridyl, 3-pyridyl, 3-pyridyl substituted at positions 2, 4, 5 or 6 with one or more groups selected from halogen, nitro, alkoxy, alkylthio, cyano, carbalkoxy, difluoromethoxy, difluoromethylthio or alkylsulfonyl; 2-thienyl, 3-thienyl, 2,1,3-benzoxadiazolyl, 2,1,3-benzthiadiazolyl or phenyl optionally substituted at positions 2 through 6 with one or more groups selected from hydrogen, alkyl, alkoxy, cyano, carbalkoxy, alkyl-thio, difluoromethoxy, difluoromethylthio, alkylsulfonyl, halo, nitro or trifluoromethyl; or the pharmaceutically acceptable acid addition salts thereof.

The compounds of this invention are assymetric in the pyridine ring at the R₃ point of attachment and thus exist as optical antipodes and as such are part of this invention. The antipodes can be separated by methods known to those skilled in the art such as, for example, fractional recrystallization of diastereomeric salts of enantiomerically pure acids. Alternatively, the antipodes can be separated by chromatography in a Pirkle column.

Also included in this invention is a process for preparing the compounds of formula I, said process being disclosed in detail hereinafter.

Also part of the present invention are certain intermediates and the process for the preparation thereof.

Preferred compounds of the present invention are:

1. Ethyl 2,3,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl) -1,2-dioxothieno[3,2-b]pyridine-6-carboxylate.

2. N,N-Dimethylaminoethyl 2,3,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl)-1,1-dioxothieno[3,2-b]pyridine-6-carboxylate.

3. N-Benzyl-N-methylaminoethyl 2,3,4,7-tetrahydro-5-methyl-7-(3-nitrophenyl)-1,1-dioxothieno [3,2-b]pyridine-6-carboxylate.

4. Ethyl 3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl) -1,1-dioxo-2H-thio-pyrano [3,2-b]pyridine-7-carboxylate.

5. N,N-Dimethylaminoethyl 3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-2H-thipyrano[3,2-b]pyridine-7-carboxylate.

6. N-Benzyl-N-methylaminoethyl 3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl) -1,1-dioxo-2H-thipyrano[3,2-b]pyridine-7-carboxylate.

7. N-Benzyl-N-methylaminoethyl 3,4,5,8-tetrahydro -6-methyl-8-(2,3,4,5,6-pentafluorophenyl)-1,1-dioxo-2H-thiopyrano[3,2-b]pyridine-7-carboxylate.

8. Ethyl 9-(2,3,4,5,6-pentafluorphenyl)-2,3,4,5,6,9 -hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

9. N-Benzyl-N-methylaminoethyl 2,4,5,6,9-hexahydro-7-methyl-9-(3-nitrophenyl)-1,1-dioxothiacyclohepteno [3,2-b]pyridine-8-carboxylate.

10. N,N-Dimethylaminoethyl 2,3,4,5,6,9-hexahydro-7-methyl -9-(3-nitrophenyl)-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

11. 2-Methoxyethyl 2,3,4,5,6,9-hexahydro-7-methyl -9-(3-nitrophenyl)-1,1-dioxo-thiacyclohepteno[3,2-b]pyridine-8-carboxylate.

12. N-Benzyl-N-methylaminoethyl 9-(2,3,4,5,6-pentafluorophenyl)-2,3,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteneo[3,2-b]pyri dine-8-carboxylate.

13. Ethyl 10-(2,3,4,5,6-pentafluorophenyl) -3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxo-2H-thiacycloocteneo[3,2-b]pyridine-9-carboxylate.

14. N-Benzyl-N-methylaminoethyl 10-(2,3,4,5, 6-pentafluorophenyl)-2,3,4,56,7,10-hexahydro-8-methyl-1,1-dioxo-2H-thiacyclooceteno[3,2-b]pyridine-9-carboxylate.

15. N-Benzyl-N-methylaminoethyl 3,4,5,6,7,10-hexahydro-8 -methyl-10-(3-nitrophenyl)-1,1-dioxo-2H-thiacycloocteno

[3,2-b]pyriein-9-carboxylate.

16. N-Benzyl-N-methylaminoethyl 11-(3-nitrophenyl) 2,3,4, 6,7,8,11-octahydro-9-methyl-1,1-dioxothiacyclononeno[3, 2-b]pyridine-10-carboxylate.

17. N-Benzyl-N-methylaminoethyl 2,4,5,6,9-hexahydro-6-methyl-9-(3-nitrophenyl)-1,1-dioxothiacyclohepteno [3,2-b][yridine-8-carboxylate.

18. N-Benzyl-N-methylaminoethyl 9-(2-chlorophenyl)-2,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno [3,2-b]pyridine-8-carboxylate.

19. N-Benzyl-N-methylaminoethyl 9-(2,3-dichlorphenyl)2,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

20. N-Benzyl-N-methylaminoethyl 9-(2-chloro-6-fluorophenyl)-2,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

21. N-Benzyl-N-methylaminoethyl 9-(2-cifluoromethoxyphenyl)-2,4,5,6,9-hexahydro-7-methyl-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

22. N-Benzyl-N-methylaminoethyl 2,4,5,6,9-hexahydro-7-methyl-9-(2-trifluoromethylphenyl)-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate.

23. N-Benzyl-N-methylaminoethyl 10-(2-chlorphenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxocycloocteno [3,2-b]pyridine-9-carboxylate.

24. N-Benzyl-N-methylaminoethyl 10-(2,3-dichlorophenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

25. N-Benzyl-N-methylaminoethyl 10-(2-difluoromethoxyphenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

26. N-Benzyl-N-methylaminoethyl 10-(2-chloro-6-fluorophenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

27. N-Benzyl-N-methylaminoethyl 10-(2-chloro-3-trifluoromethylphenyl)-3,4,5,6,7,10-hexahydro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

28. N-Benzyl-N-methylaminoethyl 12-(2-chloro-3-trifluoromethylphenyl)-2,3,4,5,6,7,8,11-octahydro-9-methyl-1,1-dioxothiacyclononeno[3,2-b]pyridine-10-carboxylate.

29. N-Methyl-N-phenylaminoethyl 10-(2,3,4,5,6-pentafluorophenyl)-3,4,5,6,7,10-hexahyro-8-methyl-1,1-dioxothiacycloocteno[3,2-b]pyridine-9-carboxylate.

The compounds of this invention are potent inhibitors of calcium ion uptake into smooth muscle tissue and act to relax or prevent contraction of tissue mediated by calcium mechanisms. The compounds of this invention have therapeutic utility in the treatment of cardiovascular disorders including hypertension, ischmeia, angina, arrhythmias, congestive heart failure, peripheral vascular disorders such as intermittant claudication, migraines, myocardial infarction, platelet aggregation and stroke.

In addition, the compounds of the invention possess utility with respect to other disorders such as hypersensitivity, allergy, asthma, dysmenorrhea, bronchoconstriction, esophageal spasm, premature labor and unirnary tract, gastric hypersecretory and membrane integrity disorders. The compounds, compositions and methods for making the various aspects of the present invention will become more readily apparent from the following description.

DESCRIPTION AND PREFERRED EMBODIMENTS

Various terms used herein should be understood to signify the following:

Unless specified otherwise, the term "alkyl" refers to a straight, branched or cyclic substituent consisting solely of carbon and hydrogen with no unsaturation and containing from 1 to 8 carbon atoms. The term "lower alkoxy" refers to a lower alkyl chain as described above having no more than 4 carbons. The term "halo" means fluoro, chloro, bromo and iodo.

The phrase "pharmaceutically acceptable salts" denotes salts of the free base which possess the desired pharmacological activity of the free base and which are neither biologically nor otherwise undesirable. These salts may be derived from inorganic or organic acids. Examples of inorganic acids are hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid or phosphoric acid. Examples of organic acids are acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like.

Pharmaceutical compositions containing a compound of the present invention as the active ingredients in intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., aerosol, intravenous, sublingual, oral or topical. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case or oral solid preparations such as, for example, powders, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantagesou oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. For aerosol use, suspension or solutions may be employed. The pharmaceutical compositions will generally contain per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, from about 0.001 to about 100 mg/kg and preferably from about 0.001 to about 20 mg/kg of the active ingredient.

The novel compounds of the present invention may be synthesized according to the following reaction scheme wherein R₁, R₂, R₃, R₄, R₅, are as defined above, MCPBA signifies m-chloroperoxybenzoic acid, and Y is p-methylphenyl or alkyl. ##STR2##

With reference to the above Reaction Scheme, the synthesis of the compounds of this invention is accomplished as follows:

The 3-keto cyclic sulfones of formula V (in the instance wherein n is 1-4) can be prepared in accordance with the procedure disclosed in B. Listert, P. Kuffner, and T. J. Arackel, Chem. Ber. 110, 1069-1085 (1977).

However, in the case of 3-oxo-tetrahydrothiophene-1, 1-dioxide, that is wherein n is 2, the reference procedure is quite laborious. It has been found, in accordance with the present invention, that the compounds of formula V, in which n is 2 or 3, can be obtained in high yield in a straightforward manner from the respective 3-cyclic sulfides of formula II. Said compound of formula II may be prepared in accordance with the procedure disclosed in E. A. Fehnel, J. Amer. Chem. Soc. 74, 1569-74 (1952).

The 3-keto moiety of compound II is reduced to an alcohol (compound III) preferably with sodium borohydride although a number of other reducing agents such as diborane, lithium aluminum hydride or sodium cyanoborohydride may be used. Thereafter compound III is oxidized to compound IV preferably with m-chloroperoxybenzoic acid. Other suitable oxidizing agents are hydrogen peroxide or sodium periodate. Finally, the hydroxy moiety on compound IV is reoxidized to the corresponding keto moiety in compound V, preferably using Jones reagent (chromic anhydride in dilute sulfuric acid which is added to a solution of the alcohol in acetone). Other suitable oxidizing agents are: potassium dichlormatic or Collins reagent (chromic anhydride in pyridine).

The 7, 8 and 9 membered 3-keto cyclic sulfones may be prepared in accordance with the method described in the Listert et al reference, previously mentioned.

Compounds of the formula I, wherein n is 1-12 (designated compound Ia in the following Reaction Scheme) may be prepared by stirring equal molar amounts of for example 3-oxotetrahydrothiophene-1,1-dioxide, the appropriately substituted aldehyde of formula VII and the substituted 3-aminoester of formula VI in ethanol for two to twenty-four hours at room temperature (see example 4). The resultant hydroxy intermediate of formula VIII is a novel compound. Said compound VIII is then heated in refluxing toluene for one to twenty-four hours to effect dehydration, thus producing compound Ia (see example 5).

The 6 to 15 membered cyclic sulfone products of formula I (wherein n is 3-12) may be obtained by refluxing a stirred ethanolic mixture of equimolar amounts of the ketosulfone of formula V, the aldehyde of formula VII and the substitited 3-aminoester of formula VI for about 16 hours in accordance with the procedure of example 6. The resultant product wherein n is 3-12, is designated compound IB and/or XII. Note that compound 1b is actually the same as compound 1a, but obtained by a different route. Where the novel compound XII is isolated, it can be converted to Ib by heating with ethanolic hydrogen chloride or toluene.

The preparation of compound I wherein R₂ is alkylene-NR₄ R₅ can also be achieved when a compound of the formula V is reacted with an appropriate aldehyde of the formula VII and 2-hydroxyethyl-3-aminocrotonate of formula VIa in order to prepare the intermediate of formula Ic (see example VIII). The latter intermediate of formula Ic is then converted to the sulfonyl ester preferably by refluxing with a compound of the formula IX, wherein Y is p-methylphenyul or alkyl. The sulfonyl ester of formula X is then displaced with an appropriate amine of formula XI in order to produce a compound of the formula Id (see example 9).

In the following examples, both example 6 and example 10 illustrate the procedure of compound Ib, by the direct reaction of compound V, compound VII and compound VI, in the instance wherein n is 3-12.

Various Reaction Schemes discussed above are disclosed in the following additional references:

G. A. Pagani, J. Chem. Soc., Perkin Trans. 2, 1392-7 (1974). K. G. Mason, M. A. Smith, and E. S. Stern, J. Chem. Soc. (C) 2171-76 (1967).

Maruko Seiyaku, Japan No. 58201764 (1984).

The following specific examples are illustrative of the present invention and should not be considered as limitative thereof in any manner.

EXAMPLES: Example 1 Tetrahydrothiopyran-3-o1

To a solution of tetrahydrothiopyran-3-one (ref 4) (10.0g, 0.086 moles) in ethanol was added sodium borohydride (3.25 g, 0.086 moles) over a 5 minute period. After stirring for 30 minutes, a 1 N. solution of hydrochloric acid was added until a pH of 5 was reached. The reaction mixture was diluted with water and extracted with dichloromethane (6×50 mL). The organic phase was dried over magnesium sulfate, filtered, concentrated in vacuo, and distilled (approx. 100 torr, 158° C.) to give 6.8 g product. H' NMR CDCl₃ 3.9 (broad singlet, 1H) 2.2-2.9 (multiplet, 5H) 1.4-2.2 (multiplet, 4H).

Example 2 Tetrahydrothiopyran-3-o1-1,1-dioxide

A solution of tetrahydrothiopyran-3-o1 (6.8 g, o.58 moles) and chloroform (250 mL) was cooled to 0° C. and treated with m-chloroperoxybenzoic acid (23.4 g, 0.135 moles) at a rate which did not cause the temperature to rise above 10° C. After addition was complete, the thickened mixture was stirred at 0° C. for 1 hour and then at room temperature for 30 minutes. The resulting solid was removed by filtration and the filtrate evaporated in vacuo. The resulting solid was diluted with ethanol and eavporated in vacuo to remove remaining chloroform. The resulting solid was diluted with water (150 mL) and filtered. The filtrate was evaporated in vacuo and residual water was removed by repeated evaporation with toluene. This afforded 7.5 g of products as a colorless oil. H' NMR D₆ -DMSO 4.3 (broad singlet, 1H) 3.4-4.0 (multiplet, 1H) 2.7-3.3 (multiplet, 4H) 1.2-2.1 (multiplet, 4H).

Example 3 Tetrahydrothiopyran-3-one-1,1-dioxide

To a solution of tetrahydrothipyran-3-o1-1,1-dioxide (7.5 g, 0.05 moles) and acetone (150 mL) was slowly added enough Jones reagent to maintain a brown color for at least 10 minutes without need for additional reagent. The excess reagent was reduced by addition of isopropanol (5 mL). The mixture was filtered through anhydrous magnesium sulfate and the chromium salts were washed 3x with acetone. The solvent was removed in vacuo to give a solid which was triturated with ethanol. The resulting crystals were isolated by filtration and rinsed 3x with diethyl ether. After drying, 5.0 g of product was obtained. H' NMR CDCl₃ 4.0 (singlet, 2H) 3.3 (triplet, 2H) 2.6 (triplet, 2H) 2.3 (multiplet, 2H).

Example 4 Methyl 2,3,3a,4,7,7a-hexahydro-3a-hydroxy-5-methyl-7-(2-nitrophenyl)-1,1-dioxo-thieno[3,2-b]pyridine-6-carboxylate

A solution fo tetrahydrothiophene-3-oxo-1,1-dioxide (1.3 g, 0.01 moles), 2-nitrobenzaldehyde (1.5 g, 0.01 moles) and methyl 3-aminocrotonate (1.1 g, 0.01 moles) in ethanol (20 mL) was stirred overnight. The resulting crystals were isolated by filtration and washed 2x with ethanol and 2x with diethyl ether. After drying under high vacuum for 24 hours 2.54 g of product was obtained, mp 175°-179° C. (dec).

Example 5 Methyl 2,3,4,7,-tetrahydro-5-methyl-7-(2-nitrophenyl) -1,1-dioxothieno[3,2-b]pyridine-6-carboxylate

A mixture of methyl 2,3,3a,4,7,7a-hexahydro-3a-hydroxy-5-methyl-7-(2-nitrophenyl)-1,1-dioxothieno [3,2-b]pyridine-6-carboxylate (2.5 g, 0.0065 moles) and toluene (60 mL) was refluxed for 24 hours. The solvent was removed in vacuo and the resulting solid was recrystallized from ethanol. The crystals were washed with diethyl ether 2x and dried at 65° C. under high vacuum for 48 hours. This gave 1.78 g product; mp 215°-217° C.

Example 6 Methyl 3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-2H-thiopyrano-[3,2-b]pyridine-7-carboxylate

A mixture of tetrahydrothiopyran-3-one-1,1-dioxide (0.830 g, 0.0056 moles), 3-nitrobenzaldehyde (0.846 g, 0.0056 moles) and methyl 3-aminocrotonate (0.644 g, 0.0056 moles) in methanol (20 mL) was refluxed for 16 hours. After cooling, the resulting solid was isolated by filtration and washed with diethyl ether. This solid was dried at 40° C. for 4 hours under vacuum to give 0.620 g product; mp 236°-238° C.

Example 7 2-Hydroxyethyl 3-Aminocrotonate

Anhydrous ammonia gas was bubbled through a solution of 2-hydroxyethyl 3-oxo-butyrate (25 g, 0.17 moles) (ref 5) and ethanol (250 mL) for 20 minutes. This solution was stirred for 16 hours at room temperature. The solvent was removed in vacuo and the resulting oil was chromatographed on silica gel (250 g) using ethyl acetate-hexane 60:40 as eluant. The enriched fractions were combined and the solvent removed in vacuo to give the product; H' NMR CDCl₃ 4.33 (t, 2H) 3.85 (t, 2H) 3.55 (s, 1H) 2.85 (broad singlet, 1H) 2.31 (s, 3H).

Example 8 2-Hydroxyethyl 3,4,5,8-tetrahydro-6-methyl-8-(3-nitrophenyl)-1,1-dioxo-2H-thiopyrano [3,2-b]pyridine-7-carboxylate

A mixture of tetrahydrothiopyran-3-one-1,1-dioxide (2.80 g, 0.0189 moles), 3-nitrobenzaldehyde (2.85 g, 0.0189 moles), 2-hydroxyethyl-3-aminocrotonate (3.28 g, 0.0226 moles), ammonium acetate (0.291 g, 0.0038 moles) and ethanol (35 mL) was refluxed for 16 hours. After cooling to room temperature the resulting solid was isolated by filtration, washed with ethanol and diethyl ether. The product was dried under vacuum for 16 hours at room temperature affording the product; mp 233°-235° C.

Example 9 N-Benzyl-N-methyl-2-aminoethyl 3,4,5,8-tetrahydro -6-methyl-8-(3-nitrophenyl)-1,1-dioxo-5H-thipyrano[3,2-b]pyridine-7-carboxylate Hemioxalate

A mixture of 2-hydroxyethyl 3,4,5,8-tetrahydro-6-methyl-8-(3-nitrphenyl)-1,1-dioxo-2H-thipyrano[3,2-b] pyridine-7-carboxylate (2.5 g, 0.0062 moles), p-toluenesulfonyl choride (4.65 g, 0.0244 moles), triethylamine (2.46 g, 0.0244 moles) and dichloromethane (25 mL) was refluxed for 4.5 hours. The reaction mixture was cooled and the solvent removed in vacuo. The resulting oil was chromatographed on silica gel (170 g) using ethyl acetate - methanol 95:5 as eluant. The enriched fractions containing the tosylate (H' NMR CDCl₃ 7.3-8.2 (multiplet, 8H) 6.9 (singlet, 1H) 5.2 (singlet, 1H) were combined and N-benzyl-N-methylamine (4.69 g, 0.0387 moles) was added to the solution. The solvent was removed in vacuo and the resulting residue was allowed to stand for 72 hours at room temperature. Chromatography of the mixture was accomplished on silica gel (170 g) using a mixture of ethyl acetate and methanol 97:3 as eluant. The isolated product was dissolved in ether and treated with a saturated solution of oxalic acid in diethyl ether. The resulting solid was collected by filtration, washed with diethyl ether and dried at 60° C. for 165 hours under vacuum affording the product (2.07 g) mp 220°-222° C.

Example 10 Ethyl 2,3,4,5,6,9-hexahydro-7-methyl-9-(3-nitrophenyl)-1,1-dioxothiacyclohepteno[3,2-b]pyridine-8-carboxylate

A solution of thiacycloheptane -3-one-1,1-dioxide (1.3 g, 0.0080 moles), 3-nitrobenzaldehyde (1.2 g, 0.0080 moles), ethyl 3-aminocrotonate (1.04 g, 0.0080 moles) and ethanol (20 mL) was refluxed 16 hours. After removal of the solvent in vacuo the residue was chromatographed on silica gel (170 g) using a mixture of ethyl acetate and hexane (4:1) as eluant. The enriched fractions were combined and the solvent removed in vacuo. The solid was triturated with diethyl ether, filtered and dried under vacuum overnight to give 1.52 g of product; mp 211°-213° C.

Example 11 Ethyl 3,4,5,7,10,10a-hexahydro-8-methyl-10-(3-nitrophenyl) -1, 1-dioxo-2H-thiacycloocteno[3,2-b]pyridine-9-carboxylate

A solution f thiacyclooctane -3-one-1,1-dioxide (0.35g, 0.002 moles), 3-nitrocrotonate (0.26 g, 0.002 moles) and ethanol (30 mL) was refluxed 16 hours. After cooling to room temperature a yellow precipitate formed which was isolated by filtration, washed with diethyl ether and dried in vacuo to afford the product (0.56g) mp 211°-214° C.

Example 12 Ethyl 3,4,5,6,7,10-hexahydro-8-methyl-10-(3-nitrophenyl -1, 1-dioxo-2H-thiacycloocteno[3,2-b]pyridine-9 -carboxylate

A mixture of ethyl 3,4,5,7,10,10a-hexahydro-8-methyl-10-(3-nitrophenyl)-1,1-dioxo-2H-thiacycloocteno[3,2-b](30 mL) was refluxed for 24 hours. The resulting solid was isolated by filtration, washed with diethyl ether and dried in vacuo to afford the product mp 234°-235° C.

The compounds of the present invention were evaluated for their biological properties. The present compounds have shown the ability to influence calcium mediated events including inhibiting of smooth muscle contraction of trachea and vascular tissues. The model screening regimen used to evaluate these compounds has shown:

(1) Inhibition of nitrendipine binding to calcium channels.

(2) Ability to modulate the activity of tissues which are dependent on calcium utilization as in trachea and vascular tissue.

(3) Their use as anithypertensives and/or bronchodilating agents in mammals.

Based on the above results, it is believed that these compounds will be useful in hypertension, mycardial, ischmeia, angina, congestive heart failure, migraine, mycardial infarction, platelet aggregation, stroke, hypersensitivity, allergy, asthma, gastric secretory dysmenorrhea, esophageal spasm, premature labor and urinary tract disorders.

The following Table 1 sets forth inhibition of nitrendipine binding as well as inhibition of calcium dependent smooth muscle contraction in terms of percent inhibition, for a number of representative compounds of the present invention.

                                      TABLE I                                      __________________________________________________________________________      ##STR3##                                                                                                                    Inhibition of                                                        Inhibition of                                                                            Ca.sup.2+  dependent                                                 Nitrendipine                                                                             smooth muscle                                                                            (μm)                N R.sub.2             R.sub.3 mp °C.                                                                        binding IC.sub.50 (μM)                                                                traction %                                                                               concentration          __________________________________________________________________________     2 CH.sub.3            C.sub.6 F.sub.5                                                                        228-231                                                                              0.15      47        2.0                    2 CH.sub.3            3-NO.sub.2C.sub.6 H.sub.4                                                              198-201                                                                              0.70      76        10.0                   2 CH.sub.3            3-ClC.sub.6 H.sub.4                                                                    196-199                                                                              0.93      --        --                     2 CH.sub.3            3-CNC.sub.6 H.sub.4                                                                    204-205                                                                              2.0       --        --                     2 CH.sub.3            2-NO.sub.2C.sub.6 H.sub.4                                                              215-217                                                                              1.35      63        2.0                    2 CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6 H.sub.5                                               3-NO.sub. 2C.sub.6 H.sub.4                                                             117-123                                                                              1.0       65        5.0                    3 CH.sub.2 CH.sub.3   2-NO.sub.2C.sub.6 H.sub.4                                                              215-217                                                                              1.5       75        10.0                   3 CH.sub.2 CH.sub.3   3-NO.sub.2C.sub.6 H.sub.4                                                              207-209                                                                              0.17      69        10.0                   3 CH.sub.3            3-NO.sub.2C.sub.6 H.sub.4                                                              236-238                                                                              0.16      57        10.0                   3 CH.sub.3            2-NO.sub.2C.sub.6 H.sub.4                                                              291-292                                                                              0.89      84        10.0                   3 CH.sub.2 C.sub.6 H.sub.5                                                                           2-NO.sub.2C.sub.6 H.sub.4                                                              123-126 dec                                                                          3.4       69        10.0                   3 CH.sub.3            C.sub.6 F.sub.5                                                                        242-244                                                                              0.40      46        0.5                    3 CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6 H.sub.5                                               3-NO.sub.2C.sub.6 H.sub.4                                                              220-222                                                                              1.85      46        2.0                    4 CH.sub.3            3-NO.sub.2C.sub.6 H.sub.4                                                              217-219                                                                              0.027, 0.039                                                                             94        2.0                    2 CH.sub.2 CH.sub.3   C.sub.6 F.sub.5                                                                        223-226                                                                              0.56      48        2.0                    4 CH.sub.2 CH.sub.3   C.sub.6 F.sub.5                                                                        202-205                                                                              0.028     95        0.5                    4 CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6 H.sub.5                                               C.sub.6 F.sub.5                                                                        160-165                                                                              0.035     74        0.2                    4 CH.sub.2 CH.sub.3   3-NO.sub.2C.sub.6 H.sub. 4                                                             211-213                                                                              0.044     96        2.0                    4 CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6 H.sub.5                                               3-NO.sub.2C.sub.6 H.sub.4                                                              123-127                                                                              0.13      68        0.2                                                  175-179 dec                                                                          56% @ 8.0 26        2.0                       ##STR4##                                                                       ##STR5##                   211-214                                                                              0.27      53%       2.0                    5 CH.sub.2 CH.sub.3   3-NO.sub.2C.sub.6 H.sub.4                                                              234-235                                                                              0.0055    71%       0.1                    __________________________________________________________________________

                                      TABLE II                                     __________________________________________________________________________      ##STR6##                                                                                                                   Inhibition                                                                              Inhibition of                                                         Trachea Muscle                                                                          Aorta Muscle                                                   Inhibition of                                                                         Contraction                                                                             Contraction                                               Mass Nitrendipine                                                                              Concen-  Concen-                                               Spectra                                                                             binding                                                                               % In-                                                                              tration                                                                             %                                                                                  tration              N R         X               MP   MH.sup.+                                                                            IC.sub.50 (μM)                                                                     hibition                                                                           (μM)                                                                             hibition                                                                           (μM)              __________________________________________________________________________     4 3-NO.sub.2 C.sub.6 H.sub.4                                                               CH.sub.2 CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6                                          190-194                                                                             540  0.29   50  2.0  25  0.1                  4 3-NO.sub.2C.sub.6 H.sub.4                                                                 ##STR7##       131-134                                                                             552  0.860  17  2.0  12  0.1                  4 3-NO.sub.2C.sub.6 H.sub.4                                                                CH.sub.2 CH.sub.2 OH                                                                           185-187                                                                             423  2.40   23  2.0  41  3.0                     ##STR8## CH.sub.2 CH.sub.3                                                                              180-185                                                                             423  0.108  79  0.3  42  0.1                  4 3-NO.sub.2C.sub.6 H.sub.4                                                                CH.sub.2 CH.sub.2 NHC.sub.6 H.sub.5                                                            147-150                                                                             498  0.016  72  1.0  48  0.1                  4 3-NO.sub.2C.sub.6 H.sub.4                                                                 ##STR9##       202-204                                                                             524  0.100  56  1.0  80  0.1                  5 3-NO.sub.2C.sub.6 H.sub.4                                                                 ##STR10##      159-165                                                                             498  0.065  53  0.1  48  0.1                  4 2-CF.sub.3C.sub.6 H.sub.4                                                                CH.sub.2 CH.sub.2 NCH.sub.3 C.sub.6 H.sub.5                                                    135-137                                                                             535  0.046  59  0.1  57  0.1                  5 2,3-Cl.sub.2C.sub.6 H.sub.3                                                              CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 CH.sub.2 C.sub.6                                          162-166                                                                             577  0.149  57  1.0  67  0.1                  4 2-NO.sub.2C.sub.6 H.sub.4                                                                CH.sub.2 CH.sub.2 NCH.sub.3 C.sub.6 H.sub.5                                                    137-140                                                                             512  0.086  57  0.1  43  0.1                  5 2-NO.sub.2 C.sub.6 H.sub.4                                                               CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6 H.sub.5                                           144-147                                                                             540  0.105  69  0.1  73  0.1                  4 3-NO.sub.2C.sub.6 H.sub.4                                                                 ##STR11##      141-145                                                                             538  0.200  45  0.2  53  0.1                  5 3-NO.sub.2C.sub.6 H.sub.4                                                                 ##STR12##      184-185                                                                             548  0.070  29  0.1  48  0.1                  4 2-NO.sub.2C.sub.6 H.sub.4                                                                CH.sub.2 CH.sub.2 CH.sub.2 NCH.sub.3 CH.sub.2 C.sub.6                                          127-130                                                                             540  1.0    41  1.0  7.7 0.1                  4 3-NO.sub.2C.sub.6 H.sub.4                                                                CH.sub.2 CH.sub.2 NCH.sub.3 C.sub.6 H.sub.5                                                    186-187                                                                             512  0.045  65  1.0  53  0.1                  5 C.sub.6 F.sub.5                                                                          CH.sub.2 CH.sub.2 NCH.sub.3 C.sub.6 H.sub.5                                                    124-126                                                                             571  0.018  47  0.1  63  0.1                  4 C.sub.6 F.sub.5                                                                           ##STR13##      243-245                                                                             524         53  2.0                           4 2,3-Cl.sub.2C.sub.6 H.sub.3                                                               ##STR14##      195-197                                                                             503         54  2.0                           __________________________________________________________________________      ##STR15##                                                                                                        Inhibition Trachea                                                                           Inhibition Aorta                                 Mass Inhibition Contraction   Contraction                                      Spectra                                                                             Nitrendipine binding                                                                      %     Concentration                                                                          %     Concentration           N R          MP    MH.sup.+                                                                            IC.sup.50 (μM)                                                                         Inhibition                                                                           (μM) Inhibition                                                                           (μM)                 __________________________________________________________________________     4 2-CF.sub.3C.sub.6 H.sub.4                                                                 101-104                                                                              549  0.16       64    0.1     85    0.1                     4 2-Cl, 6-FC.sub.6 H.sub.3                                                                  156-162                                                                              533  0.029      50    0.1     66    0.1                     4 2,5-F.sub.2C.sub.6 H.sub.3                                                                152-160                                                                              517  0.12       43    0.1     47    0.1                     4 2,3-Cl.sub.2C.sub.6 H.sub.3                                                               150-157                                                                              549  0.10       62    0.1     83    0.1                     4 3-CF.sub.3C.sub.6 H.sub.4                                                                 117-120                                                                              549  2.8        37    0.2     44    0.1                     4 2-FC.sub.6 H.sub.4                                                                        137-140                                                                              499  0.44       84    2.0     32    0.1                     4 2-NO.sub.2C.sub.6 H.sub.4                                                                 144-147                                                                              526  0.44       49    0.1     44    0.1                     5 C.sub.6 F.sub.5                                                                           181-184                                                                              585  0.087      50    0.1     70    0.1                     4 2-Cl, 5-NO.sub.2C.sub.6 H.sub.3                                                           170-173                                                                              560  0.26       38    0.1     63    0.1                     4 2-ClC.sub.6 H.sub.4                                                                       128-134                                                                              515  0.22       57    0.1     54    0.1                     4 2-Cl, 3-CF.sub.3C.sub.6 H.sub.3                                                           168-172                                                                              583  0.39       50    0.2     66    0.1                     5 2-Cl, 3-CF.sub.3C.sub.6 H.sub.3                                                           165-175                                                                              597  0.20       57    0.1     78    0.1                     5 3-NO.sub.2C.sub.6 H.sub.4                                                                 150-154                                                                              540  0.045      43    0.1     67    0.1                     5 2,3-Cl.sub.2C.sub.6 H.sub.3                                                               155-160                                                                              563  0.075      26    0.1     58    0.1                     5 2-NO.sub.2C.sub.6 H.sub.4                                                                 144-147                                                                              540  0.11       48    0.1     73    0.1                     6 2-Cl, 3-CF.sub.3C.sub.6 H.sub.3                                                           150-155                                                                              611  0.47       46    2.0     30    0.1                     4 2,6-Cl.sub.2C.sub.6 H.sub.3                                                               160-165                                                                              549  0.086      55    0.1     50    0.1                     5 2-OCHF.sub.2C.sub.6 H.sub.4                                                               88-91 561  0.095      76    0.1     80    0.01                    4 2-OCHF.sub.2C.sub.6 H.sub.4                                                               130-134                                                                              547  0.072      54    0.1                                   __________________________________________________________________________

The assay for inhibition of nitrendipine binding follows the following procedure:

Female, New Zealand white rabbits (1-2 kg) are sacrificed by cervical dislocation, and the heart is immediately removed, cleaned, and chopped into small pieces. The tissue is homogenized in 5X volume of 0.05M Hepes buffer, pH 7.4. The homogenate is centrifuged at 4000 xg for 10 minutes; the supernatant is recentrifuged at 42,000 xg for 90 minutes. The resulting membrane pellet is resuspended (0.7 ml/g weight) in 0.05M Hepes, pH 7.4 and stored at -70° C. until used. Each tube of the binding assay contains ³ H-nitrendipine (0.05-0.50nM), buffer, membranes (0.10 ml), and test compound in a total volume of 1.0 ml. After 90 minutes at 4° C., the bound nitrendipine is separated from the unbound by filtration on Whatman GF/C fibers. After rinsing, the filters are dried and counted in a liquid scintillation counter.

Non-specific binding of ³ H-nitrendipine (that amount bound in the presence of excess unlabelled nitrendipine) is subtracted from the total bound to obtain specifically bound radiolabeled nitrendipine. The amount of specifically bound nitrendipine in the presence of a test compound is compared to that amount bound in the absence of a compound. A percent displacement (or inhibition) can then be obtained.

The test for inhibition of calcium dependent smooth muscle contraction is determined according to the following procedure:

Trachea from dogs sacrificed by excess KCl injection are stored overnight at 4° C. in oxygenated Krebs-Henseleit buffer. Tracheal rings, one cartilage segment wide (5-10 mm), are cut starting from the bronchial end. After cutting the cartilage, the trachealis muscle tissue is suspended in oxygenated Krebs-Henseleit buffer at 37° C. in a 25 ml tissue bath. After a 60 minutes equilibration period, the tissues are challenged with 10 uM carbachol. After 5 minutes the tissues are rinsed and allowed to rest 50 minutes. The tissues are then challenged with 50 mM KCl and, after 30 minutes, the contractions are quantitated. The tissues are then rinsed and reequilibrated for 50 minutes. Test compounds are then added for 10 minutes, and the tissue is rechallenged with 50 mMKcl. After 30 minutes, the contraction is recorded and used to determine the % inhibition of control.

The percent inhibition of smooth muscle contracting is calculated from response data before and after drug treatment. ##EQU1## A rating is assigned to the compound depending upon the percent inhibition obtained. 

We claim:
 1. A process for preparing a compound of the formula ##STR16## wherein n is an integer from 1 to 12; R₁ is hydrogen, amino, alkyl, haloalkyl or CH₂ OR₂ ; R₂ is straight chained or branched alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, or alkylene-X, wherein X is alkoxy, hydroxy, halo, p-tosyloxy, mesyloxy, pyridyl, amino or --NR₄ R₅, wherein R₄ and R₅ are the same or different and are selected from hydrogen, alkyl, cycloalkyl, phenyl, benzyl, phenylethyl, or R₄, R₅ and the nitrogen atom to which they are attached form a 5, 6 or 7 membered heterocyclic ring which optionally contains an oxygen or sulfur atom or an additional nitrogen atom, or said heterocyclic ring may be fused to a benzene ring, and in the instance wherein said heterocyclic ring is piperazino, said piperazino may optionally be substituted in the 4- position with the substituent R₆ which is selected from alkyl, cycloalkyl, benzyl, phenyl, or phenyl substituted by alkoxy, halo, alkyl, nitro or trifluoromethyl; R₃ is 2-pyridyl, 3-pyridyl, 3-pyridyl substituted at positions 2, 4, 5 or 6 with one or more groups selected from halogen, nitro, alkoxy, alkylthio, cyano, carbalkoxy, difluoromethoxy, difluoromethylthio or alkylsulfonyl; 2-thienyl, 3-thienyl, 2,1,3-benzoxadiazolyl, 2,1,3-benzthiadiazolyl or phenyl optionally substituted at positions 2 through 6 with one or more groups selected from hydrogen, alkyl, alkoxy, cyano, carbalkoxy, alkylthio, difluoromethoxy, difluoromethylthio, alkylsulfonyl, halo, nitro or trifluoromethyl; or the pharmaceutically acceptable acid and base addition salts thereof;which process comprises reacting a compound of the formula (V) ##STR17## with a compound of formula (VI) ##STR18## and a compound of the formula R₃ CHO (VII), to prepare a compound of the formula (VIII); ##STR19## in the instance wherein n is 2, and thereafter dehydrating said compound (VIII) in order to prepare compound of the formula (Ia) ##STR20## or to prepare a compound of the formula (XII) ##STR21## in the instance wherein N is 3-12, by reacting a compound of the formula (V) ##STR22## with a compound of the formula (VI) ##STR23## and a compound of the formula (VII)

    R.sub.3 CHO                                                (VII)

to form a compound of the formula (XII) ##STR24## and thereafter, if desired, converting compound XII to compound Ib by heating compounds XII with ethanolic hydrogen chloride or toluene to form a compound of the formula (Ib) ##STR25## or in the instance wherein it is desired to prepare a final compound of the formula (Id) ##STR26## reacting a compound of the formula (V) with a compound of the formula (VIa) ##STR27## and a compound of the formula R₃ CHO (VII) in order to prepare a compound of the formula (Ic) ##STR28## then reacting said compound (Ic) with a compound of the formula YSO₂ Cl, wherein Y is p-methylphenyl or alkyl, in order to prepare a compound of the formula (X) ##STR29## and thereafter reacting said compound (X) with a compound of the formula HNR₄ R₅ (XI) to prepare a compound of the formula (Id) ##STR30## wherein in formulas Id, VIa, Ic and X represents an ethylene moiety. 